The present invention relates to inhibiting the growth of bFGF-dependent neoplastic cells and more particularly, to reducing the growth of a specific type of neoplastic cells, i.e. human glioma cells.
Neoplasm, or aberrant, uncontrolled growth patterns of abnormal tissue is an undesirable condition. Substantial research has been performed on neoplastic cells with the ultimate goal being to inhibit or reduce growth of such cells.
The present invention will be described in the context of human glioma cells but may be applicable to other neoplastic cells as well. Also by way of background, basic fibroblast growth factor will be discussed briefly because the present invention centers on the use of bFGF-specific antisense primer (also referred to herein as bFGF-specific oligonucleotide).
It is known that bFGF is a heparin-binding, multifunctional protein that has until now been recognized primarily for its mitogenic and angiogenic properties. On the basis of cell culture studies, bFGF has been shown to be mitogenic for a wide range of cell types derived from mesoderm and neuroectoderm. In addition to the many in vitro studies performed with bFGF, it is also active in numerous in vivo models of angiogenesis and wound healing. bFGF has been identified in many normal and malignant tissues and at several developmental time points, implying that it may play a role in normal tissue function, embryonic development and neoplastic progression.
The mammalian central nervous system (CNS) is a particularly abundant source of bFGF. Substantial quantities of bFGF have been purified from whole brain extracts, hypothalamus and retina. Despite its abundance in neural tissue, a precise cellular localization for bFGF synthesis in brain has not been unequivocally determined. bFGF immunoreactivity has been localized to neurons, in vitro and in vivo by immunocytochemical analysis. In a more recent survey, enhanced bFGF immunoreactivity was observed in brain regions enriched in neurons. In contrast, bFGF has also been identified in cultured mouse cerebellar astroglia and in reactive rat astrocytes surrounding a focal suction wound to the brain.
Based on the above-described studies, I concluded that astrocytes, or star-shaped neurological cells, may represent a potential source of bFGF expression in the CNS under appropriate circumstances. This conclusion is consistent with the recent identification of bFGF in human glial tumors and in transformed human glial cell lines. In addition to expressing bFGF, human glioma cells respond to it with increased proliferation, suggesting that bFGF may be involved in an autocrine pathway regulating glioma growth and invasion.
Due to its multifunctional properties bFGF could potentially influence glioma development by directly stimulating tumor cell growth or by promoting tumor vascularization. bFGF and related members of the FGF family have been implicated in the autocrine regulation of human tumor growth based partly on transfection studies with bFGF expression vector, which result in amplified autocrine growth in monolayer culture and soft agar.
The overexpression of growth factors and their receptors has been implicated in the genesis and maintenance of a variety of human neoplasms. The putative growth factor receptor c-neu (c-erbB-2), has been detected in a significant number of human breast carcinomas while the epidermal growth factor (EGF) receptor is amplified in approximately 30-40% of human gliomas. Amplication of bFGF-related int-2 and host genes has also been observed in a small percentage of breast tumors.
An object of the present invention is to alter bFGF expression in human glioma cells as a way of ultimately inhibiting growth of such cells.
Another object of the present invention is to alter bFGF expression in human glioma cells as a way of ultimately changing the malignancy behavior of such cells.